was cooled to 20 °C, and methylene chloride (109 kg) was
added. The organic layer was separated, and the aqueous
layer was extracted with methylene chloride (61.7 kg). The
collected organic layer was extracted with 1 N NaOH
solution (89.7 kg). The separated aqueous layer was washed
two times with methylene chloride (91 kg × 2). To the
separated aqueous layer was added dropwise a solution of 6
N HCl (18.98 kg), and the mixture was extracted two times
with methylene chloride (90 and 50.2 kg, respectively). The
combined organic layers were passed through silica gel (12.3
kg) and eluted with methylene chloride (40 L). The eluent
was concentrated in vacuo until the mixture volume reached
about 50 L. The residue was diluted with carbon tetrachlo-
ride33 (53.02 kg) and hexane (59 kg). Concentration of the
mixture was continued until about 50 L of distillate was
collected. Hexane (20 L) was added, and the mixture was
stirred for 30 min. The formed solid was filtered, washed
with hexane (20 L), and dried under nitrogen purge to afford
6.66 kg (65.3%) of product 9 of 83% ee. HPLC analysis
(Chiralcel OJ, 210 nm, 1.0 mL/min, hexane/ethanol/trifluo-
roacetic acid ) 50/50/1 (v/v), 9 at 6.0 min, (R)-isomer of 9
at 9.7 min, and trans-9 at 13.9 min) showed 88.0% of 9,
8% of (R)-isomer of 9 and 4% of trans-9. Spectroscopic data
separated and washed with 10% Na2SO3 (1000 mL) solution
and H2O (1000 mL). The separated organic layer was
concentrated (950 mL of CH2Cl2 was distilled), and MTBE
(1000 mL) was added to the residue. After stirring for 5 h,
the formed solid was filtered and washed with MTBE (100
mL). The filter cake was dried with nitrogen purge to give
90.2 g (60% yield) of 17R as a white solid. Spectroscopic
data of 17R: 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J )
7.8 Hz, 2H), 7.59 (t, J ) 7.4, 1H), 7.48 (t, J ) 7.8 Hz, 2H),
7.36-7.19 (m, 10H), 6.60 (s, 1H), 5.55 (dd, J ) 4.6, 4.2
Hz, 1H), 5.12 (s, 2H), 5.02 (br. 1H), 3.79 (m, 1H), 3.30 (m,
1H), 3.08 (m, 1H), 3.02 (dd, J ) 7.8, 4.1 Hz, 1H), 2.88 (dd,
J ) 13.3, 7.8 Hz, 1H), 2.30 (dd, J ) 14.7, 7.8 Hz, 1H), 2.17
(m, 1H), 2.02 (dd, J ) 15.6, 4.2 Hz, 1H), 0.98 (d, J ) 6.4
Hz, 3H), 0.76 (d, J ) 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 199.1, 169.5, 155.9, 136.5, 135.4, 133.8, 129.6,
128.9, 128.8, 128.7, 128.6, 128.2, 127.1, 67.0, 58.2, 58.0,
54.3, 51.6, 39.5, 35.4, 31.7, 20.1, 16.9; HRMS calcd for
C31H35N2O5 (M + 1) 515.2546, found 515.2536.
1
Spectroscopic data of 17â: H NMR (500 MHz, CDCl3)
δ 7.97 (d, J ) 7.4 Hz, 2H), 7.58 (m, 1H), 7.47 (m, 2H),
7.35-7.20 (m, 10H), 6.98 (br, 1H), 5.60 (dd, J ) 9.2, 4.6
Hz, 1H), 5.03 (dd, J ) 19.7, 12.4 Hz, 2H), 4.79 (d, J ) 8.7
Hz, 1H), 3.72 (m, 1H), 3.40 (dd, J ) 9.7, 6.0 Hz, 1H), 3.09
(dd, J ) 14.2, 4.1 Hz, 1H), 2.92 (dd, J ) 10.7, 7.1 Hz, 2H),
2.87 (dd, J ) 9.7, 4.2 Hz, 1H), 2.67 (m, 1H), 2.21 (m, 1H),
1.01 (d, J ) 6.9 Hz, 3H), 0.83 (d, J ) 6.9 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 199.3, 169.9, 156.0, 136.3, 136.0,
135.5, 133.7, 129.6, 128.8, 128.7, 128.6, 128.2, 127.1, 67.2,
58.3, 58.1, 55.7, 49.8, 38.5, 36.0, 31.6, 20.1, 17.0.
Spectroscopic data of 18: 1H NMR (500 MHz, CDCl3)
δ 7.97 (d, J ) 7.4 Hz, 2H), 7.61 (m, 1H), 7.49 (t, J ) 7.8
Hz, 2H), 7.33-7.17 (m, 5H), 6.78 (d, J ) 8.7 Hz, 1H), 5.58
(dd, J ) 8.7, 4.1 Hz, 1H), 5.30 (s, 1H), 4.27 (dd, J ) 5.1,
3.2 Hz, 1H), 4.13 (m, 1H), 3.99 (d, J ) 9.2 Hz, 1H), 2.91
(dd, J ) 13.3, 5.1 Hz, 1H), 2.83 (dd, J ) 13.3, 8.2 Hz, 1H),
2.67 (dd, J ) 15.1, 9.6 Hz, 1H), 2.45 (dd, J ) 15.6, 3.2 Hz,
1H), 2.19 (m, 1H), 1.00 (d, J ) 6.9 Hz, 3H), 0.76 (d, J )
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 199.2, 171.3,
136.0, 135.3, 133.9, 129.1(×2), 129.0, 128.7, 127.4, 83.0,
68.6, 58.3, 54.9, 42.0, 38.3, 31.7, 20.1, 16.7; MS (CI) m/z
425 (M+ + 1).
(3S,4R)-Epoxy-(5S)-[[N-[(1-methylethoxy)carbonyl]-3-
(methyl-sulfonyl)-L-valinyl]-amino]-N-[2-methyl-(1R)-
[(phenyl)-carbonyl]propyl]-6-phenylhexanamide (LB71350).
To a stirred solution of 17R (3.20 kg, 6.22 mol) in methanol
(10.28 kg) and THF (2.96 kg) was added Pd/C (228 g,
Degussa E101NE/W, 10% Pd, 58 wt %) at room temperature.
The mixture was blanketed with hydrogen using hydrogen
control box (pressure 0.1-0.15 kgf/cm2), and stirring was
continued for 15 h. The catalyst was filtered through Celite,
and the filter cake was washed with THF (10 L). After the
filtrate was concentrated, acetonitrile (3.68 kg) was added
to the residue, and the mixture was concentrated again in
vacuo. HPLC analysis of the residue showed 74.3% of 19,
1.5% of 19-OH, and 1.2% of 17R.
1
of 9: H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 7.36-
7.17 (m, 10H), 5.54-5.50 (m, 1H), 5.48-5.41 (m, 1H), 4.96
(dd, J ) 16.4, 12.8 Hz, 2H), 4.39 (ddd, J ) 14.4, 7.2, 7.2
Hz, 1H), 2.99 (dd, J ) 17.6, 6.4 Hz, 1H), 2.80 (m, 2H),
2.64 (dd, J ) 13.2, 6.4 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 172.2, 155.2, 138.1, 137.1, 132.5, 129.2, 128.2,
128.0, 127.6, 127.5, 126.0, 122.9, 65.0, 49.9, 40.4, 32.3; mp
90-91 °C.
(5S)-[N-(Benzyloxycarbonyl)-amino]-(3S,4R)-epoxy-N-
[2-methyl-(1R)-[(phenyl)carbonyl]-propyl]-6-phenylhex-
anamide (17R). To a stirred solution of 9 (100 g, 0.295 mol,
1.0 equiv) in CH2Cl2 (1000 mL) was added HOBT (43.8 g,
0.32 mol, 1.1 equiv) at room temperature. The mixture was
cooled to 5-10 °C. DIC (50.8 mL, 0.32 mol, 1.1 equiv)
was added dropwise, maintaining the reaction temperature
below 15 °C. After addition, the reaction mixture was
allowed to warm to room temperature and stirred for an
additional 30 min. The mixture was cooled to 5-10 °C.
N-methylmorpholine (48.6 mL, 0.442 mol, 1.5 equiv) and
phenylvalinone hydrochloride (66.1 g, 0.31 mol, 1.05 equiv)
were added to the mixture, maintaining the reaction tem-
perature below 15 °C. After 5 h, 1 N NaOH solution (750
mL) was added to the mixture, and the formed solid was
filtered. The filter cake was washed with CH2Cl2 (200 mL).
The organic layer was separated from the filtrate and washed
with 0.5 N NaOH solution (750 mL) and 0.5 N HCl solution
(750 mL) in sequence. To the separated organic layer were
added UHP (124.7 g, 1.33 mol, 4.5 equiv) and Na2HPO4
(177.8 g, 1.252 mol, 4.25 equiv). The mixture was cooled
to -5 °C, and TFAA (83.2 mL, 0.59 mol, 2.0 equiv) was
added over 30 min, maintaining the reaction temperature
below -5 °C. After 1 h at -5 °C, 0.5 N NaOH (1000 mL)
solution was added to the mixture. The organic layer was
To a stirred solution of 5 (2.74 kg, 5.92mol) in methylene
(33) Carbon tetrachloride is harmful to liver, kidney, and central nervous system.
Exposure to 1000-2000 ppm for 30-60 min can be fatal to humans.
chloride (23 kg) were added dropwise N-methylmorpholine
844
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Vol. 7, No. 6, 2003 / Organic Process Research & Development